Review

Application of Nanotechnology in Cancer Diagnosis and

Therapy - A Mini-Review

Cancan Jin1, Kankai Wang2, Anthony.Oppong-Gyebi3, Jiangnan Hu3*

[1] Department of Oncology, Affiliated Dongyang People’s Hospital of Wenzhou Medical

University, Dongyang, Zhejiang 322100,China

[2] Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University,

Wenzhou, Zhejiang 325000, China

[3] Department of Pharmacology and Neuroscience, University of North Texas Health Science

Center, Fort Worth, Texas 76107, USA

Cancan Jin, j445742262@hotmail.com

Kankai Wang, neurowkk@163.com

Anthony.Oppong-Gyebi, Anthony.Oppong-Gyebi@my.unthsc.edu

Jiangnan Hu, jiangnan.hu@unthsc.edu

*Corresponding Authors.

ABSTRACT

Cancer is a leading cause of death and poor quality of life globally. Even though several

strategies are devised to reduce deaths, reduce chronic pain and improve the quality of life, there

remains a shortfall in the adequacies of these cancer therapies. Among the cardinal steps towards

ensuring optimal cancer treatment are early detection of cancer cells and drug application with

high specificity to reduce toxicities. Due to increased systemic toxicities and refractoriness with

conventional cancer diagnostic and therapeutic tools, other strategies including nanotechnology

are being employed to improve diagnosis and mitigate disease severity. Over the years,

immunotherapeutic agents based on nanotechnology have been used for several cancer types to

reduce the invasiveness of cancerous cells while sparing healthy cells at the target site.

Nanomaterials including carbon nanotubes, polymeric micelles and liposomes have been used in

cancer drug design where they have shown considerable pharmacokinetic and pharmacodynamic

benefits in cancer diagnosis and treatment. In this review, we outline the commonly used

nanomaterials which are employed in cancer diagnosis and therapy. We have highlighted the

suitability of these nanomaterials for cancer management based on their physicochemical and

biological properties. We further reviewed the challenges that are associated with the various

nanomaterials which limit their uses and hamper their translatability into the clinical setting in

certain cancer types.

Keywords: nanomaterials, nanotechnology, cancer, diagnosis, treatment.

Introduction

Cancer is a leading cause of death and a global health burden. It was estimated that there would

be 18.1 million new cancer cases and 9.6 million cancer-related deaths by 2018[1]. Cancer is a

disease characterized by uncontrolled cell proliferation that spreads from an initial focal point to

other parts of the body to cause death. For these reasons, it is key to ensure earlier detection and

treatment of cancers to reduce disease spread and mortalities. Amongst the widely used strategies,

today in cancer research is nanotechnology. Nanotechnology has led to several promising results

with its applications in the diagnosis and treatment of cancer, including drug delivery[2], gene

therapy, detection and diagnosis, drug carriage, biomarker mapping, targeted therapy, and

molecular imaging. Nanotechnology has been applied in the development of nanomaterials[3],

such as gold nanoparticles and quantum dots, which are used for cancer diagnosis at the

molecular level. Molecular diagnostics based on nanotechnology, such as the development of

biomarkers, can accurately and quickly detect the cancers[4]. Nanotechnology treatments, such

as the development of nanoscale drug delivery, can ensure precise cancerous tissue targeting with

minimal side effects[5, 6]. Due to its biological nature, nanomaterials can easily cross cell

barriers[7]. Over the years, nanomaterials have been used in the treatment of tumors, due to their

active and passive targeting. Although many drugs can be used to treat cancers, the sensitivity of

the drugs generally leads to inadequate results and can have various side effects, as well as

damage to the healthy cells. In view of that, several studies have examined different forms of

nanomaterials, such as liposomes, polymers, molecules, and antibodies, with the conclusion that

a combination of these nanomaterials in cancer drug design can achieve a balance between

increasing efficacy and reducing the toxicity of drugs[8]. However, due to the potential toxicity

of nanomaterials, there is still a lot of advancement to be done on them before their readily

acceptance in the clinic for cancer management[9]. With the rapid development of

nanotechnology, this paper will review its application in cancer diagnosis and treatment with

focus on their benefits and limitations during use (Figure 1).

Figure 1. Application of nanomaterials in cancer diagnosis and therapy.

1. NANOTECHNOLOGY IN CANCER DIAGNOSIS

Genetic mutations can cause changes in the synthesis of certain biomolecules leading to

uncontrolled cell proliferation and ultimately cancerous tissues[7]. Cancers can be classified as

either benign or malignant. Benign tumors are confined to the origin of cancer while malignant

tumors actively shed cells that invade surrounding tissues as well as distant organs. Cancer

diagnostic and therapeutic strategies are targeted at early detection and inhibition of cancerous

cell growth and their spread. Notable among the early diagnostic tools for cancers is the use of

positron emission tomography (PET), magnetic resonance imaging (MRI), computed

tomography (CT) and ultrasound[10]. These imaging systems, however, are limited by their

inadequate provision of relevant clinical information about different cancer types and the stage.

Hence it makes it difficult to obtain a full evaluation of the disease state based on which an

optimum therapy can be provided [11, 12].

1.1 Nanotechnology aids in tumor imaging

In the past few decades, the application of nanoparticles in cancer diagnosis and monitoring has

attracted a lot of attention with several nanoparticle types being used today for molecular

imaging. Due to their advantages including small size, good biocompatibility, and high atomic

number, they have gained prominence in recent cancer research and diagnosis. Nanoparticles

used in cancer such as semiconductors, quantum dots and iron oxide nanocrystals possess optical,

magnetic or structural properties that are less common in other molecules [13]. Different

anti-tumor drugs and biomolecules including peptides, antibodies or other chemicals, can be used

with nanoparticles to label highly specific tumors, which are useful for early detection and

screening of cancer cells[14].

For cancer diagnostics, imaging of tumor tissue with nanoparticles has made it possible to detect

cancer in its early stages. In lung cancer, the detection of metastases can be determined by

developing immune superparamagnetic iron oxide nanoparticles (SPIONs) that can be used in

MRI imaging with the cancer cell lines as the target for the SPIONs [15]. Recent studies have

shown a high specificity of SPIONs with no known side effects, making them suitable building

blocks for aerosols in lung cancer MRI imaging[16-18][19].

Magnetic powder imaging has also been used in tomographic imaging technology where it has

shown a high resolution and sensitivity to cancer tissues[20]. In animal experiments, nebulization

of the lungs has been achieved using magnetic nanoparticles (MNPs) with Epidermal growth

factor receptor (EGFR), a commonly expressed protein in non-small cell lung cancer (NSCLC)

cases as a target. Further, in vitro studies using nanosystem for positron emission tomography

(PET) have also been developed based on self-assembled amphiphilic dendritic molecules. These

dendritic molecules spontaneously assemble into uniform supramolecular nanoparticles with

abundant PET reporting units on the surface. By taking advantage of dendritic multivalence and

the enhanced penetration and retention (EPR) effect, the dendritic nanometer system effectively

accumulates in tumors, resulting in extremely sensitive and specific imaging of various tumors

while reducing treatment toxicities.

1.2. Nanotechnology Tools Used in Cancer Diagnosis

In current research, nanotechnology can validate cancer imaging at the tissue, cell, and molecular

levels[20]. This is achieved through the capacity of nanotechnology applications to explore the

tumor's environment, For instance, pH- response to fluorescent nanoprobes can help detect

fibroblast activated protein-a on the cell membrane of tumor-associated fibroblasts[21]. Hereon,

we will discuss some nanotechnology-based spatial and temporal techniques that can help

accurately track living cells and monitor dynamic cellular events in tumors.

1.2.1 Near Infrared (NIR) Quantum Dots

The lack of ability to penetrate objects limits the use of visible spectral imaging. Quantum dots

that emit fluorescence in the near-infrared spectrum (i.e., 700-1000 nanometers) have been

designed to overcome this problem, making them more suitable for imaging colorectal cancer,

liver cancer, pancreatic cancer, and lymphoma[22-24]. A second near-infrared (NIR) window

(NIR-ii, 900-1700 nm) with higher tissue penetration depth, higher spatial and temporal

resolution has also been developed to aid cancer imaging. Also, the development of a

silver-rich Ag2Te quantum dots (QDs) containing a sulfur source has been reported to allow

visualization of better spatial resolution images over a wide infrared range[25].

1.2.2. Nanoshells

Another commonly used nanotechnology application is the use of nanoshells. Nanoshells are

dielectric cores between 10 and 300 nanometers in size, usually made of silicon and coated with

a thin metal shell (usually gold)[26, 27]. These nanoshells work by converting plasma-mediated

electrical energy into light energy and can be flexibly tuned optically through UV-infrared

emission/absorption arrays. Nanoshells are desirable because their imaging is devoid of the

heavy metal toxicity[28] even though their uses are limited by their large sizes.

1.2.3. Colloidal Gold Nanoparticles

Gold nanoparticle (AuNPs) is a good contrast agent because of its small size, good

biocompatibility, and high atomic number. Research shows that AuNPs work by both active and

passive ways to target cells. The principle of passive targeting is governed by a gathering of the

gold nanoparticles to enhance imaging because of the permeability tension effect (EPR) in tumor

tissues[29]. Active targeting, on the other hand, is mediated by the coupling of AuNPs with

tumor-specific targeted drugs, such as EGFR monoclonal antibodies, to achieve AuNP active

targeting of tumor cells (Figure 2). When the energy exceeds 80kev, the mass attenuation rate of

gold becomes higher than alternative elements like iodine, indicating a greater prospect gold

nanoparticles [30]. Rand et al. mixed AuNPs with liver cancer cells and found that using X-ray

imaging, the clusters of liver cancer cells in the gold nanocomposite group were significantly

stronger than those in the liver cancer cells alone. These findings have important implications for

early diagnosis, with the technique allowing tumors as small as a few millimeters in diameter to

be detected in the body[31].

1.3. Nanotechnology used in cancer biomarker screening

Cancer biomarkers are biological features whose expression indicates the presence or state of a

tumor. Such markers are used to study cellular processes, to monitor or identify changes in

cancer cells, and these results could ultimately lead to a better understanding of tumors.

Biomarkers can be proteins, protein fragments or DNA. Among them, tumor biomarkers, which

are indicators of a tumor, can be tested to verify the presence of specific tumors. Tumor

biomarkers ideally should possess a high sensitivity (>75%) and specificity (99.6%)[32]. Under

current medical conditions, biomarkers from blood, urine, or saliva samples are used to screen

individuals for cancer risk. But these biomarkers have not proven adequate for cancer screening.

Therefore, several researchers have resorted to the study of extract patterns of abnormally

expressed proteins, peptide fragments, glycans and autoantibodies from serum, urine, ascites or

tissue samples from cancer patients[33-35]. With the development of proteomics technology,

protein biomarkers for many cancers have been discovered.

In general, protein profiling tests would remove the high molecular weight proteins such as

albumin and immunoglobulins. However, the removal of these proteins also removes the low

molecular weight protein biomarkers conjugated to them, resulting in the loss of the biomarkers

of interest. These low molecular weight proteins represent a potential biomarker-rich

population[36-38]. Two studies led by Geho and Luchini came up with the method of capturing

and enriching low molecular weight proteins by nanoparticles to obtain biomarkers from

biological liquids, thus improving the screening of biomarkers[39, 40]. Nanoparticles compete

with the carrier proteins by their surface characteristics, such as electric charge, or functional

biomolecules, which are currently possessed by mesoporous silica particles, hydrogel

nanoparticles, and carbon nanotubes[39-46].

Another method to improve screening with nanocarrier is to improve the sensitivity of mass

spectrometry. The unique optical and thermal properties of carbon nanotubes enhance the

energy-transfer efficiency of the analyte, contributing to the absorption and ionization of the

analyte, and eliminate the interference of inherent matrix ions[46-48]. A third approach is to use

nanotechnology to make lab-on-chip microfluidics devices that can be used for

immuno-screening or to study the properties of tumor cells. For example, a system showing great

promise is lab-on-a-chip for high performance multiplexed protein detection using quantum dots

made of cadmium selenide (CdSe) core with a zinc sulfide (ZnS) shell linked to antibodies to

carcinoembryonic antigen, cancer antigen 125 and Her-2/Neu[49]. Another example is that cells

growing on the surface of different sized nanometres, which were discovered by these

nanometres across can differentiate between tumor cells[50]. Suffice it to say that there are still

false-positive and false-negative results from screening of biomarkers by nanotechnology, and

we need to improve sensitivity without compromising specificity.

Figure 2. Various types of gold nanoparticles (different sizes, morphologies, and ligands)

accumulate in tumor tissues by the action of osmotic tension effect (termed Passive targeting) or

localize to specific cancer cells in a ligand-receptor binding way (termed Active targeting).

2. NANOTECHNOLOGY IN CANCER THERAPY

2. 1. Tools of Nanotechnology for Cancer Therapy

The development of nanotechnology is based on the usage of small molecular structures and

particles as tools for delivering drugs. Nano-carriers such as liposomes, micelles, dendritic

macromolecules, quantum dots, and carbon nanotubes have been widely used in cancer

treatment.

2. 1. 1. Liposomes

Liposomes are one of the most studied nanomaterials, which are nanoscale spheres composed of

natural or synthesized phospholipid bilayer membrane and water phase nuclei[51]. Because of

the amphiphilicity of phospholipids, liposomes form spontaneously[51], allowing hydrophilic

drugs to preferentially stay in the monolayer liposome while hydrophobic ones form before the

multilayer liposome[52]. Some drugs could be incorporated into liposomes by exchanging them

from acidic buffer to the neutral buffer. Neutral drugs can be transported in liposomes also, but

due to a poor avidity for acidic environments, they are not readily released from the inside of the

liposomes[53]. Other mechanisms of drug delivery are the combination of saturated drugs with

organic solvents to form liposomes[51]. Under the influence of the EPR effect[53], the vesicle of

size around 4000 kDa or 500 nm can be allowed into the tumor by the gaps in vessels[52]. In

tumors they can fuse with cells, are internalized by endocytosis, and release drugs in the

intracellular space[52]. In the case of the appropriate pH�redox potential�ultrasonic and under

the electromagnetic field, the liposome can also release the drug through passive or active

ligand-mediated activity[52]. The targeted therapy has an advantage in the vascular system,

micrometastases, and blood cancers[54]. It has been shown that the half-life of liposome is

affected by size. The liposome up to 100 nanometers easily penetrate the tumor and stay longer,

while the half-life of the bigger liposome is shorter because they are easily recognized and

cleared by the mononuclear phagocyte system[55]. Liposome-bound antibodies target

tumor-specific antigens to ensure active targeting and then transport drugs to the tumor. With a

lot of pharmacokinetic benefits, some liposomal drugs are approved for clinical therapy (Table

1). For instance, liposomal forms of adriamycin have been used for the management of

metastatic ovarian cancer where they have shown appreciable clinical benefit[56, 57].

2. 1. 2. Carbon Nanotubes

Based on the structure and the diameter, Carbon nanotubes (CNTs) can be categorized

into two kinds, the single-walled CNTs (SWNTs) and the multiwalled CNTs (MWNTs)[58]. The

SWNTs are composed of monolithic cylindrical graphene, and the MWNTs are composed of

concentric graphene[58]. Because of the physical and chemical properties of carbon nanotubes,

that include surface area, mechanical strength, metal properties, electrical and thermal

conductivity, it is a candidate well suited for large-scale biomedical applications[59]. Carbon

nanotubes also possess a property that allows them to absorb light from the near-infrared (NIR)

region, causing the nanotubes to heat up by the thermal effect, hence can target tumor

cells[60-62]. The natural forms of carbon nanotubes promote noninvasive penetration of biofilms

and are regarded as highly competent carriers for the transport of various drug molecules into

living cells[63]. Due to the suitability of carbon nanotubes, drugs such as paclitaxel are

assembled with them and administered both in vitro and in vivo for cancer treatment[64].

2.1.3. Polymeric Micelles

Polymeric nanoparticles (PNPs) are the inventions that relate to a solid micelle with a particle

size range of 10-1000nm[65]. PNPs are collectively known as polymer nanoparticle,

nanospheres, nanocapsules or polymer micelles and they were the first polymers reported for drug

delivery systems. PNPs serve as drug carriers for hydrophobic drugs and are widely used for

drug discovery [66-68]. The PNPs constructed from amphiphilic polymers with a hydrophilic

and hydrophobic block can perform rapid self-assembly because of the hydrophobic interactions

in an aqueous solution[69]. The PNPs can capture the hydrophobic drugs because of a covalent

bond or the interaction via a hydrophobic core. Thus, to carry the hydrophilic charged molecules,

such as proteins, peptides, and nucleic acids, these blocks are switched to allow interactions in

the core and neutralize the charge[67]. The advantages of the higher thermodynamic stability and

the smaller volume make the PNPs a suitable drug carrier with good endothelial cell permeability

while avoiding kidney rejection[70-73]. The hydrophobic macromolecules and drugs can be

transferred to the center of the PNPs, hence, the injection of PNPs suspension after being

separated in an aqueous solution could achieve therapeutic effect[73]. Importantly, by oral or

parenteral administration, drugs can reach the target cells in different ways, potentially provide

alternative ways to lower cytotoxicity in healthy tissues compared to the cancer cells. However,

the major challenges in the use of PNPs for cancer nanomedicine still exist in how to effectively

deliver the drugs to the target site with limited side effects or drug resistance. Recently, the PNPs

have been used widely in the nanotechnology-based cancer drug design due to their excellent

potential benefits for patient care. For example, adriamycin conjugated nanomaterial was used to

treat several types of cancers where it achieved therapeutic effects to a decent degree. However,

it also presented with many side-effects, such as toxicity and heart problems, thereby limiting its

use. Such problems are overcome by Doxil (a liposomal form of doxorubicin), which is less

associated with cardiotoxicity in patients, and hence may provide a safer nanomaterial synthetic

approach for researchers in the future[74-77].

2.1.4. Dendrimers

The dendrimers are nanocarriers that have a spherical polymer core with regularly spaced

branches[78]. As the dendritic macromolecule diameter increases, the tendency to tilt towards a

spherical structure increases[79]. There are usually two ways to synthesize dendrimers, a

divergent method in which the dendrimers can grow outward from the central nucleus, and a

convergence method, where the dendrimers grow inward from the edges and end up in the

central nucleus[80, 81]. Various molecules including polyacrylamide, polyglycerol-succinic acid,

polylysine, polyglycerin, poly2, 2bis(hydroxymethyl) propionic acid, and melamine are

commonly used to form dendrimers[82]. These dendritic macromolecules exhibit different

chemical structures and properties, such as alkalinity, hydrogen bond capacity and charge, which

can be regulated by growing dendritic macromolecules or changing the groups on the surface of

dendritic macromolecules. In general, the dendritic drug conjugates are formed by the covalent

binding of antitumor drugs to dendritic peripheral groups[83]. Thus, several drug molecules can

attach to each dendritic molecule and the release of these therapeutic molecules is controlled in

part by the nature of the attachment. The physicochemical and biological properties of the

polymer including the size, charge, multi-ligand groups, lipid bilayer interactions, cytotoxicity,

internalization, plasma retention time, biological distribution, and filtration of dendritic

macromolecules, have made dendrimers potential nanoscale carriers[81]. Several studies have

further shown that cancer cells with a high expression of folate receptors could form foils from

dendritic molecules bound to folate[84-86]. An added advantage of dendrimers is their ability to

bind to DNA as seen with the DNA-polyamides clustering DNA-poly(amidoamine)

(DNAPAMAM), making them highly effective at killing cancer cells that express the folate

receptor[87].

2.1.5. Quantum Dots

Quantum dots (QDs) are small particles or nanocrystals of semiconductor materials between 2

and 10 nanometers in size[88]. The ratio of the height of the surface to the volume of these

particles gives the QDs the intermediate electron property which is between a mass

semiconductor and a discrete atom[89]. Over the years, various QDs based techniques such as

modification of QD conjugates and QD immunostaining have been developed. With the

improvement of multiplexing capability, QDs conjugation greatly exceeds the monochromatic

experiment in both time and cost-effectiveness[90]. Moreover, at low protein expression levels

and in a low context, QD immunostaining is more accurate than traditional immunochemical

methods. In cancer diagnosis, QD immunostaining is a potential tool for the detection of various

tumor biomarkers, such as a cell protein or other components of a heterogeneous tumor

sample[91]. Quantum dots can gather in specific parts of the body and transfer the drugs to those

parts. The ability of the QDs to concentrate in a single internal organ makes them a potential

solution against untargeted drug delivery, and possibly avoid the side effects of chemotherapy.

The latest advancement in surface modification of QDs, which combine with biomolecules,

including peptides and antibodies, in vivo, can be used to target tumors and make possible their

potential applications in cancer imaging and treatment. Some studies combine QDs with

prostate-specific antigen to label cancer, while others use QDs to make biomarkers that speed up

the process with such immune markers having a more stable light intensity than traditional

fluorescent immunomarkers[92]. High sensitivity probes based on quantum dots have been

reported for multicolor fluorescence imaging of cancer cells in vivo and can also be used to

detect ovarian cancer marker cancer antigen 125 (CA125) in different types of specimens (such

as fixed cells, tissue sections, and xenograft) [93]. Besides, the light stability of quantum dot

signals is more concrete and brighter than that of traditional organic dyes[94]. Chen et al.

successfully detected BC using quantum-dot-based probes, confirming that unlike traditional

immunohistochemistry, quantum dot immunohistochemistry (IHC) can detect the very low

expressions of Human Epidermal Growth Factor Receptor 2 (HER2) as well as multichannel

detection[95, 96].

Conclusion and Future directions

Nanotechnology has shown a lot of promise in cancer therapy over the years. By their improved

pharmacokinetic and pharmacodynamic properties, nanomaterials have contributed to improved

cancer diagnosis and treatment. Nanotechnology allows targeted drug delivery in affected organs

with minimal systemic toxicities due to their specificities. However, as with other therapeutic

options, nanotechnology is not completely devoid of toxicities and comes with few challenges

with its use including systemic and certain organ toxicities, hence, causing setbacks with their

clinical applications. Given the limitations with nanotechnology, more advancements must be

done to improve drug delivery, maximize their efficacy while keeping the disadvantages to the

minimum. By improving the interactions between the physicochemical properties of the

nanomaterials employed, safer and more efficacious derivatives for diagnosis and treatment can

be made available for cancer management. In sum, we sought to highlight the key advantages of

nanotechnology and the shortfalls in their use to meet clinical needs for cancer. Adding to that,

the therapeutic benefits of nanotechnology and future advancements could make them a

therapeutic potential to be applied in other disease conditions. These may include ischemic

stroke and rheumatoid arthritis which would require targeted delivery of a suitable

pharmacologic agent at the affected site.

List of Abbreviations

AuNPs = Gold Nanoparticles

BC = Breast Cancer

CA125 = Cancer Antigen 125

CdSe= cadmium selenide

CNTs =Carbon Nanotubes

CT = Computed Tomography

DNAPAMAM = DNA-poly(amidoamine)

EGFR = Epidermal Growth Factor Receptor

HER2 =Human Epidermal Growth Factor Receptor 2

IHC = Immunohistochemistry

MNPs = Magnetic Nanoparticles

MWNTs = Multiwalled Carbon Nanotubes

MRI = Magnetic Resonance Imaging

NIR = Near Infrared

NSCLC = Non-small Cell Lung Cancer

PET = Positron Emission Tomography

PNPs = Polymeric Nanoparticles

QDs = Quantum Dots

SPIONs =Superparamagnetic Iron Oxide Nanoparticles

SWNTs = Single-walled Carbon Nanotubes

ZnS = zinc sulfifide

Contributions

CJ and JH wrote the first draft. CJ, KW, AG and JH revised and edited the final manuscript. JH

supervised the manuscript and provided critical input. All authors gave feedback and agreed on

the final version of the manuscript.

Funding

This work was supported by the Affiliated Dongyang People’s Hospital of Wenzhou Medical

University and the Neurobiology of Aging and Alzheimer’s Disease Training Program for JH

(T32 AG020494).

Table 1. Nanomaterial-carrying drugs in clinical trials of cancer treatment in the past five years.

Year Drugs Disease Findings Reference

Liposome 2015 Doxorubicin Platinum-Sensitive Ovarian Cancer favorable risk-benefit profile [97]

Paclitaxel Non-Small Cell Lung Cancer considerable disease response and

resection rate, with acceptable toxicity

[98]

Ursolic acid Advanced Solid Tumors tolerable, manageable toxicity,

improving patient remission rates

[99]

Mitomycin C advanced cancer long circulation time, tolerable�

effective

[100]

2016 miR-34a Mimic Advanced Solid Tumors effective [101]

Vincristine Sulfate Refractory Solid Tumors or

Leukemias

without dose-limiting neurotoxicity [102]

5-fluorouracil and

Leucovorin

Advanced Solid Tumors lower peak plasma concentration,

longer half-life, and increased area

[103]

Cytarabine Childhood Acute Lymphoblastic

Leukemia

no permanent adverse neurological

sequelae

[104]

2017 Amphotericin Acute Lymphoblastic Leukaemia effective [105]

Irinotecan Recurrent High-Grade Glioma no unexpected toxicities [106]

2018 Cytarabine and

Daunorubicin

Newly Diagnosed Secondary Acute

Myeloid Leukemia

significantly longer survival rate [107]

Curcumin Locally Advanced or Metastatic

Cancer

durable [108]

Daunorubicin Pediatric Relapsed/Refractory Acute

Myeloid Leukemia

well-tolerated and showed high

response rates

[109]

Lipovaxin-MM Malignant Melanoma well-tolerated and without clinically

significant toxicity

[110]

Vincristine Sulfate Acute Lymphoblastic Leukemia provided a meaningful clinical benefit

and safety

[111]

Oligodeoxynucleotide Refractory or Relapsed

Haematological Malignancies

well-tolerated, effective [112]

2019 Eribulin Solid Tumours well-tolerated with a favorable

pharmacokinetic profile

[113]

Polymeric

Micelles

2017 Epirubicin Solid tumors Well tolerated in patients with various

solid tumors and exhibited less

toxicity than conventional epirubicin

formulations

[114]

2018 Genexol-PM plus

carboplatin

Ovarian Cancer Non-inferior efficacy and

well-tolerated toxicities

[115]

2019 Paclitaxel (PTX) Breast cancer NK105 had a better PSN toxicity

profile than PTX

[116]

References 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN

estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:

394-424.

2. Hu J, HuangW, Huang S, ZhuGe Q, Jin K, Zhao Y.Magnetically active Fe3O4 nanorods loaded with tissue

plasminogenactivatorforenhancedthrombolysis.NanoResearch.2016;9:2652-61.

3. HuangL,HuJ,HuangS,WangB,Siaw-DebrahF,NyanzuM,etal.NanomaterialApplicationsforNeurological

DiseasesandCentralNervousSystemInjury.ProgNeurobiol.2017.

4. TranS,DegiovanniPJ,PielB,RaiPJC,MedicineT.Cancernanomedicine: a reviewof recent success indrug

delivery.2017;6:44.

5. HuangD,WuK, Zhang Y,Ni Z, ZhuX, ZhuC, et al. RecentAdvances in Tissueplasminogen activator-based

nanothrombolysisforischemicstroke.2019;58:159.

6. HuJ,HuangS,ZhuL,HuangW,ZhaoY,JinK,etal.TissuePlasminogenActivator-PorousMagneticMicrorods

forTargetedThrombolyticTherapyafterIschemicStroke.ACSApplMaterInterfaces.2018;10:32988-97.

7. ChaturvediVK,SinghA,SinghVK,SinghMP.CancerNanotechnology:ANewRevolutionforCancerDiagnosis

andTherapy.Currentdrugmetabolism.2019;20:416-29.

8. YeF, ZhaoY, El-SayedR,MuhammedM,HassanMJNT.Advances innanotechnology for cancerbiomarkers.

2018;18:103-23.

9. BharaliDJ,MousaSA.Emergingnanomedicines forearlycancerdetectionand improvedtreatment:current

perspectiveandfuturepromise.Pharmacology&therapeutics.2010;128:324-35.

10. KimD,JeongYY,JonSJAN.ADrug-LoadedAptamer?GoldNanoparticleBioconjugateforCombinedCTImaging

andTherapyofProstateCancer.2010;4:3689-96.

11. AkhterS,AhmadI,AhmadMZ,RamazaniF,SinghA,RahmanZ,etal.Nanomedicinesascancertherapeutics:

currentstatus.Currentcancerdrugtargets.2013;13:362-78.

12. WangJ,SuiM,FanW.Nanoparticlesfortumortargetedtherapiesandtheirpharmacokinetics.Currentdrug

metabolism.2010;11:129-41.

13. Popescu RC, Fufă MO, Grumezescu AM. Metal-based nanosystems for diagnosis. Romanian journal of

morphologyandembryology=Revueroumainedemorphologieetembryologie.2015;56:635-49.

14. SinghR.Nanotechnologybasedtherapeuticapplication incancerdiagnosisandtherapy.3Biotech.2019;9:

415.

15. WanX,SongY,SongN,LiJ,YangL,LiY,etal.Thepreliminarystudyofimmunesuperparamagneticironoxide

nanoparticlesforthedetectionoflungcancerinmagneticresonanceimaging.Carbohydrateresearch.2016;419:

33-40.

16. SherryAD,WoodsM.Chemicalexchangesaturationtransfercontrastagentsformagneticresonanceimaging.

Annualreviewofbiomedicalengineering.2008;10:391-411.

17. KimHS,OhSY, JooHJ,SonKR,Song IC,MoonWK.TheeffectsofclinicallyusedMRIcontrastagentsonthe

biologicalpropertiesofhumanmesenchymalstemcells.NMRinbiomedicine.2010;23:514-22.

18. Jafari A, SaloutiM, Shayesteh SF, Heidari Z, Rajabi AB, Boustani K, et al. Synthesis and characterization of

Bombesin-superparamagnetic ironoxidenanoparticles as a targeted contrast agent for imagingofbreast cancer

usingMRI.Nanotechnology.2015;26:075101.

19. Stocke NA, Meenach SA, Arnold SM, Mansour HM, Hilt JZ. Formulation and characterization of inhalable

magnetic nanocompositemicroparticles (MnMs) for targeted pulmonary delivery via spray drying. International

journalofpharmaceutics.2015;479:320-8.

20. Garrigue P, Tang J, Ding L, Bouhlel A, TintaruA, Laurini E, et al. Self-assembling supramolecular dendrimer

nanosystemforPET imagingoftumors.ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesof

America.2018;115:11454-9.

21. Ji T, ZhaoY,Wang J, ZhengX, TianY, ZhaoY, et al. Tumor Fibroblast SpecificActivationof aHybrid Ferritin

Nanocage-BasedOpticalProbeforTumorMicroenvironmentImaging.2013;9:2427-31.

22. Parungo CP,Ohnishi S, DeGrand AM, Laurence RG, Soltesz EG, Colson YL, et al. In vivo optical imaging of

pleuralspacedrainagetolymphnodesofprognosticsignificance.Annalsofsurgicaloncology.2004;11:1085-92.

23. Gao X, Cui Y, Levenson RM, Chung LW, Nie S. In vivo cancer targeting and imaging with semiconductor

quantumdots.Naturebiotechnology.2004;22:969-76.

24. DubertretB,SkouridesP,NorrisDJ,NoireauxV,BrivanlouAH,LibchaberA. Invivo imagingofquantumdots

encapsulatedinphospholipidmicelles.Science(NewYork,NY).2002;298:1759-62.

25. Zhang Y, Yang H, An X,Wang Z, Yang X, YuM, et al. Controlled Synthesis of Ag(2) Te@Ag(2) S Core-Shell

QuantumDotswithEnhancedandTunableFluorescenceintheSecondNear-InfraredWindow.Small(Weinheiman

derBergstrasse,Germany).2020;16:e2001003.

26. Hirsch LR, Stafford RJ, Bankson JA, Sershen SR, Rivera B, Price RE, et al. Nanoshell-mediated near-infrared

thermaltherapyoftumorsundermagneticresonanceguidance.ProceedingsoftheNationalAcademyofSciences

oftheUnitedStatesofAmerica.2003;100:13549-54.

27. Loo C, Lin A, Hirsch L, Lee MH, Barton J, Halas N, et al. Nanoshell-enabled photonics-based imaging and

therapyofcancer.Technologyincancerresearch&treatment.2004;3:33-40.

28. Nunes T, Pons T, Hou X, Van Do K, Caron B, RigalM, et al. Pulsed-laser irradiation ofmultifunctional gold

nanoshells toovercometrastuzumabresistance inHER2-overexpressingbreastcancer. Journalofexperimental&

clinicalcancerresearch:CR.2019;38:306.

29. FuN, Hu Y, Shi S, Ren S, LiuW, Su S, et al. Au nanoparticles on two-dimensionalMoS(2) nanosheets as a

photoanodeforefficientphotoelectrochemicalmiRNAdetection.TheAnalyst.2018;143:1705-12.

30. Fu F, Li L, LuoQ, LiQ,GuoT, YuM,et al. Selectiveand sensitivedetectionof lysozymebasedonplasmon

resonance light-scattering of hydrolyzed peptidoglycan stabilized-gold nanoparticles. The Analyst. 2018; 143:

1133-40.

31. Shrivas K, Nirmalkar N, Thakur SS, DebMK, Shinde SS, Shankar R. Sucrose capped gold nanoparticles as a

plasmonicchemicalsensorbasedonnon-covalentinteractions:ApplicationforselectivedetectionofvitaminsB(1)

andB(6)inbrownandwhitericefoodsamples.Foodchemistry.2018;250:14-21.

32. DasPM,BastRC,Jr.Earlydetectionofovariancancer.BiomarkMed.2008;2:291-303.

33. KukC,KulasingamV,GunawardanaCG,SmithCR,BatruchI,DiamandisEP.Miningtheovariancancerascites

proteomeforpotentialovariancancerbiomarkers.MolCellProteomics.2009;8:661-9.

34. FredoliniC,MeaniF,LuchiniA,ZhouW,RussoP,RossM,etal.Investigationoftheovarianandprostatecancer

peptidomeforcandidateearlydetectionmarkersusinganovelnanoparticlebiomarkercapturetechnology.AAPSJ.

2010;12:504-18.

35. DiMicheleM,MarconeS,CicchillittiL,DellaCorteA,FerliniC,ScambiaG,etal.Glycoproteomicsofpaclitaxel

resistance in human epithelial ovarian cancer cell lines: towards the identification of putative biomarkers. J

Proteomics.2010;73:879-98.

36. GehoDH,LiottaLA,PetricoinEF,ZhaoW,AraujoRPJCOiCB.Theamplifiedpeptidome:thenewtreasurechest

ofcandidatebiomarkers.2006;10:50-5.

37. ZhouM,LucasDA,ChanKC,IssaqHJ,PetricoinEF,3rd,LiottaLA,etal.Aninvestigationintothehumanserum

"interactome".Electrophoresis.2004;25:1289-98.

38. Merrell K, Southwick K, Graves SW, Esplin MS, Thulin CDJJoBTJ. Analysis of Low-Abundance,

Low-Molecular-WeightSerumProteinsUsingMassSpectrometry.2005;15:238-48.

39. GehoDH,JonesCD,PetricoinEF,LiottaLA.Nanoparticles:potentialbiomarkerharvesters.Currentopinionin

chemicalbiology.2006;10:56-61.

40. LuchiniA,FredoliniC,EspinaBH,MeaniF,ReederA,RuckerS,etal.Nanoparticletechnology:addressingthe

fundamentalroadblockstoproteinbiomarkerdiscovery.Currentmolecularmedicine.2010;10:133-41.

41. Terracciano R, Pasqua L, Casadonte F, Frascà S, PreianòM, Falcone D, et al. Derivatizedmesoporous silica

beadsforMALDI-TOFMSprofilingofhumanplasmaandurine.Bioconjugatechemistry.2009;20:913-23.

42. MeaniF,PecorelliS,LiottaL,PetricoinEF.Clinicalapplicationofproteomicsinovariancancerpreventionand

treatment.Moleculardiagnosis&therapy.2009;13:297-311.

43. LongoC, PatanarutA,George T, BishopB, ZhouW, Fredolini C, et al. Core-shell hydrogel particles harvest,

concentrateandpreservelabilelowabundancebiomarkers.PloSone.2009;4:e4763.

44. GaspariM,Ming-ChengChengM, TerraccianoR, Liu X,NijdamAJ,Vaccari L, et al.Nanoporous surfaces as

harvesting agents formass spectrometric analysis of peptides in human plasma. Journal of proteome research.

2006;5:1261-6.

45. TerraccianoR,GaspariM,TestaF,PasquaL,TagliaferriP,ChengMM,etal.Selectivebindingandenrichment

for low-molecular weight biomarker molecules in human plasma after exposure to nanoporous silica particles.

Proteomics.2006;6:3243-50.

46. Najam-ul-HaqM, Rainer M, Szabó Z, Vallant R, Huck CW, Bonn GK. Role of carbon nano-materials in the

analysis of biological materials by laser desorption/ionization-mass spectrometry. Journal of biochemical and

biophysicalmethods.2007;70:319-28.

47. Xu S, Li Y, ZouH,Qiu J,Guo Z,GuoB. Carbonnanotubes as assistedmatrix for laser desorption/ionization

time-of-flightmassspectrometry.Analyticalchemistry.2003;75:6191-5.

48. Wang CH, Li J, Yao SJ, Guo YL, Xia XH. High-sensitivity matrix-assisted laser desorption/ionization Fourier

transformmass spectrometryanalysesof small carbohydratesandaminoacidsusingoxidizedcarbonnanotubes

preparedbychemicalvapordepositionasmatrix.Analyticachimicaacta.2007;604:158-64.

49. JokerstJV,RaamanathanA,ChristodoulidesN,FlorianoPN,PollardAA,SimmonsGW,etal.Nano-bio-chipsfor

highperformancemultiplexedproteindetection:determinationsof cancerbiomarkers in serumand salivausing

quantumdotbioconjugatelabels.Biosensors&bioelectronics.2009;24:3622-9.

50. HungYC,PanHA,TaiSM,HuangGS.Ananodeviceforrapidmodulationofproliferation,apoptosis, invasive

ability,andcytoskeletalreorganizationinculturedcells.Labonachip.2010;10:1189-98.

51. Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in

cancer.Trendsinpharmacologicalsciences.2009;30:592-9.

52. BozzutoG,MolinariA.Liposomesasnanomedicaldevices. International journalofnanomedicine.2015;10:

975-99.

53. FenskeDB,CullisPR.Liposomalnanomedicines.Expertopinionondrugdelivery.2008;5:25-44.

54. Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Advanced drug

deliveryreviews.2013;65:36-48.

55. Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical

applications,existingandpotential.Internationaljournalofnanomedicine.2006;1:297-315.

56. BergerJL,SmithA,ZornKK,SukumvanichP,OlawaiyeAB,KelleyJ,etal.Outcomesanalysisofanalternative

formulationofPEGylatedliposomaldoxorubicininrecurrentepithelialovariancarcinomaduringthedrugshortage

era.OncoTargetsandtherapy.2014;7:1409-13.

57. ChouH,LinH,LiuJM.AtaleofthetwoPEGylatedliposomaldoxorubicins.OncoTargetsandtherapy.2015;8:

1719-20.

58. KesharwaniP, IyerAK.Recentadvances indendrimer-basednanovectors for tumor-targeteddrugandgene

delivery.Drugdiscoverytoday.2015;20:536-47.

59. Bianco A, Kostarelos K, Prato M. Applications of carbon nanotubes in drug delivery. Current opinion in

chemicalbiology.2005;9:674-9.

60. BrennanME,ColemanJN,DruryA,LahrB,KobayashiT,BlauWJ.NonlinearphotoluminescencefromvanHove

singularitiesinmultiwalledcarbonnanotubes.Opticsletters.2003;28:266-8.

61. KamNW,O'ConnellM,Wisdom JA,DaiH.Carbonnanotubesasmultifunctionalbiological transportersand

near-infraredagentsforselectivecancercelldestruction.ProceedingsoftheNationalAcademyofSciencesofthe

UnitedStatesofAmerica.2005;102:11600-5.

62. BurlakaA,LukinS,PrylutskaS,RemeniakO,PrylutskyyY,ShubaM,etal.Hyperthermiceffectofmulti-walled

carbonnanotubes stimulatedwithnear infrared irradiation foranticancer therapy: invitro studies.Experimental

oncology.2010;32:48-50.

63. Yu X, Gao D, Gao L, Lai J, Zhang C, Zhao Y, et al. Inhibiting Metastasis and Preventing Tumor Relapse by

Triggering Host Immunity with Tumor-Targeted Photodynamic Therapy Using Photosensitizer-Loaded Functional

Nanographenes.ACSnano.2017;11:10147-58.

64. KarnatiKR,WangY.Understandingtheco-loadingandreleasingofdoxorubicinandpaclitaxelusingchitosan

functionalized single-walled carbon nanotubes by molecular dynamics simulations. Physical chemistry chemical

physics:PCCP.2018;20:9389-400.

65. Couvreur P. Polyalkylcyanoacrylates as colloidal drug carriers. Critical reviews in therapeutic drug carrier

systems.1988;5:1-20.

66. DuncanR.Thedawningeraofpolymertherapeutics.NaturereviewsDrugdiscovery.2003;2:347-60.

67. Miyata K, Christie RJ, Kataoka KJR, Polymers F. Polymeric micelles for nano-scale drug delivery. 2011; 71:

227-34.

68. BlancoE,BeyEA,KhemtongC,YangSG,Setti-GuthiJ,ChenH,etal.Beta-lapachonemicellarnanotherapeutics

fornon-smallcelllungcancertherapy.Cancerresearch.2010;70:3896-904.

69. Tian C, Feng J, Cho HJ, Datta SS, Prud'homme RK. Adsorption and Denaturation of Structured Polymeric

NanoparticlesatanInterface.Nanoletters.2018;18:4854-60.

70. Nakanishi T, Fukushima S, Okamoto K, Suzuki M, Matsumura Y, Yokoyama M, et al. Development of the

polymermicelle carrier system for doxorubicin. Journal of controlled release : official journal of the Controlled

ReleaseSociety.2001;74:295-302.

71. SavicR,LuoL,EisenbergA,MaysingerD.Micellarnanocontainersdistributetodefinedcytoplasmicorganelles.

Science(NewYork,NY).2003;300:615-8.

72. Jones M, Leroux J. Polymeric micelles - a new generation of colloidal drug carriers. European journal of

pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische

VerfahrenstechnikeV.1999;48:101-11.

73. SungJC,PulliamBL,EdwardsDA.Nanoparticlesfordrugdeliverytothelungs.Trendsinbiotechnology.2007;

25:563-70.

74. DavisME,ChenZG,ShinDM.Nanoparticletherapeutics:anemergingtreatmentmodalityforcancer.Nature

reviewsDrugdiscovery.2008;7:771-82.

75. Berry G, Billingham M, Alderman E, Richardson P, Torti F, Lum B, et al. The use of cardiac biopsy to

demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal

doxorubicin.Annalsofoncology:officialjournaloftheEuropeanSocietyforMedicalOncology.1998;9:711-6.

76. Ewer MS, Martin FJ, Henderson C, Shapiro CL, Benjamin RS, Gabizon AA. Cardiac safety of liposomal

anthracyclines.Seminarsinoncology.2004;31:161-81.

77. Sharma G, Anabousi S, Ehrhardt C, Ravi Kumar MN. Liposomes as targeted drug delivery systems in the

treatmentofbreastcancer.Journalofdrugtargeting.2006;14:301-10.

78. Svenson S, Tomalia DA. Dendrimers in biomedical applications--reflections on the field. Advanced drug

deliveryreviews.2005;57:2106-29.

79. Svenson SN, Tomalia DAJADDR. Dendrimers in biomedical applications—reflections on the field. 2005; 57:

2106-29.

80. Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S, et al. Dendritic macromolecules: synthesis of

starburstdendrimers.1986;19:2466-8.

81. Tomalia DAH, Baker H, Dewald JR, Hall MJ, Smith PBJPJ. A New Class of Polymers: Starburst-Dendritic

Macromolecules.1985;17:117-32.

82. PalmerstonMendesL,Pan J,TorchilinVP.DendrimersasNanocarriers forNucleicAcidandDrugDelivery in

CancerTherapy.Molecules(Basel,Switzerland).2017;22.

83. Sherje AP, Jadhav M, Dravyakar BR, Kadam D. Dendrimers: A versatile nanocarrier for drug delivery and

targeting.Internationaljournalofpharmaceutics.2018;548:707-20.

84. WienerEC,KondaS,ShadronA,BrechbielM,GansowO.Targetingdendrimer-chelatestotumorsandtumor

cellsexpressingthehigh-affinityfolatereceptor.Investigativeradiology.1997;32:748-54.

85. Quintana A, Raczka E, Piehler L, Lee I,Myc A,Majoros I, et al. Design and function of a dendrimer-based

therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharmaceutical research. 2002; 19:

1310-6.

86. KonoK,LiuM,Fréchet JM.Designofdendriticmacromoleculescontaining folateormethotrexate residues.

Bioconjugatechemistry.1999;10:1115-21.

87. Roy R, Baek MG. Glycodendrimers: novel glycotope isosteres unmasking sugar coding. case study with

T-antigenmarkersfrombreastcancerMUC1glycoprotein.Journalofbiotechnology.2002;90:291-309.

88. Ekimov AI, Onushchenko AAJJL. Quantum Size Effect in Three-Dimensional Microscopic Semiconductor

Crystals.1981;34:363.

89. Kastner,MarcAJPT.ArtificialAtoms.1993;46:24.

90. Shiohara A, Hoshino A, Hanaki K, Suzuki K, Yamamoto K. On the cyto-toxicity caused by quantum dots.

Microbiologyandimmunology.2004;48:669-75.

91. XiangQM,WangLW,YuanJP,ChenJM,YangF,LiY.Quantumdot-basedmultispectralfluorescentimagingto

quantitativelystudyco-expressionsofKi67andHER2inbreastcancer.Experimentalandmolecularpathology.2015;

99:133-8.

92. Ruan Y, Yu W, Cheng F, Zhang X, Rao T, Xia Y, et al. Comparison of quantum-dots- and

fluorescein-isothiocyanate-basedtechnologyfordetectingprostate-specificantigenexpression inhumanprostate

cancer.IETnanobiotechnology.2011;5:47.

93. Medintz IL, Uyeda HT, Goldman ER, Mattoussi H. Quantum dot bioconjugates for imaging, labelling and

sensing.Naturematerials.2005;4:435-46.

94. Wang HZ, Wang HY, Liang RQ, Ruan KC. Detection of tumor marker CA125 in ovarian carcinoma using

quantumdots.ActabiochimicaetbiophysicaSinica.2004;36:681-6.

95. SungSY,SuYL,ChengW,HuPF,ChiangCS,ChenWT,etal.GrapheneQuantumDots-MediatedTheranostic

PenetrativeDeliveryofDrugandPhotolytics inDeepTumorsbyTargetedBiomimeticNanosponges.Nanoletters.

2019;19:69-81.

96. ChenC,PengJ,XiaHS,YangGF,WuQS,ChenLD,etal.Quantumdots-basedimmunofluorescencetechnology

forthequantitativedeterminationofHER2expressioninbreastcancer.Biomaterials.2009;30:2912-8.

97. MahnerS,MeierW,duBoisA,BrownC,LorussoD,Dell'AnnaT,etal.Carboplatinandpegylated liposomal

doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: results from a

subsetanalysisoftheCALYPSOphaseIIItrial.Europeanjournalofcancer(Oxford,England:1990).2015;51:352-8.

98. LuB, Sun L, YanX,Ai Z, Xu J. Intratumoral chemotherapywithpaclitaxel liposomecombinedwith systemic

chemotherapy:anewmethodofneoadjuvantchemotherapyforstageIIIunresectablenon-smallcelllungcancer.

Medicaloncology(Northwood,London,England).2015;32:345.

99. QianZ,WangX,SongZ,ZhangH,ZhouS,ZhaoJ,etal.AphaseItrialtoevaluatethemultiple-dosesafetyand

antitumoractivityofursolicacidliposomesinsubjectswithadvancedsolidtumors.BioMedresearchinternational.

2015;2015:809714.

100.Golan T, Grenader T, Ohana P, Amitay Y, Shmeeda H, La-Beck NM, et al. Pegylated liposomalmitomycin C

prodrugenhancestoleranceofmitomycinC:aphase1studyinadvancedsolidtumorpatients.Cancermedicine.

2015;4:1472-83.

101.BegMS,BrennerAJ,SachdevJ,BoradM,KangYK,StoudemireJ,etal.PhaseIstudyofMRX34,a liposomal

miR-34amimic,administeredtwiceweeklyinpatientswithadvancedsolidtumors.Investigationalnewdrugs.2017;

35:180-8.

102.ShahNN,MerchantMS,ColeDE,JayaprakashN,BernsteinD,DelbrookC,etal.VincristineSulfateLiposomes

Injection(VSLI,Marqibo®):ResultsFromaPhaseIStudyinChildren,Adolescents,andYoungAdultsWithRefractory

SolidTumorsorLeukemias.Pediatricblood&cancer.2016;63:997-1005.

103.ChiangNJ,ChaoTY,HsiehRK,WangCH,WangYW,YehCG,etal.Aphase Idose-escalationstudyofPEP02

(irinotecan liposome injection) incombinationwith5-fluorouraciland leucovorin inadvancedsolid tumors.BMC

cancer.2016;16:907.

104.LevinsenM,Harila-Saari A, Grell K, JonssonOG, TaskinenM, Abrahamsson J, et al. Efficacy and Toxicity of

Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia. Journal of

pediatrichematology/oncology.2016;38:602-9.

105.Cornely OA, Leguay T, Maertens J, Vehreschild M, Anagnostopoulos A, Castagnola C, et al. Randomized

comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic

leukaemia.TheJournalofantimicrobialchemotherapy.2017;72:2359-67.

106.Clarke JL, Molinaro AM, Cabrera JR, DeSilva AA, Rabbitt JE, Prey J, et al. A phase 1 trial of intravenous

liposomalirinotecaninpatientswithrecurrenthigh-gradeglioma.Cancerchemotherapyandpharmacology.2017;

79:603-10.

107.Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin)

LiposomeforInjectionVersusConventionalCytarabinePlusDaunorubicininOlderPatientsWithNewlyDiagnosed

SecondaryAcuteMyeloidLeukemia.Journalofclinicaloncology:officialjournaloftheAmericanSocietyofClinical

Oncology.2018;36:2684-92.

108.GreilR,Greil-ResslerS,WeissL,SchönliebC,MagnesT,RadlB,etal.Aphase1dose-escalationstudyonthe

safety,tolerabilityandactivityofliposomalcurcumin(Lipocurc(™))inpatientswithlocallyadvancedormetastatic

cancer.Cancerchemotherapyandpharmacology.2018;82:695-706.

109.vanEijkelenburgNKA,RascheM,GhazalyE,DworzakMN,KlingebielT,RossigC,etal.Clofarabine,high-dose

cytarabineandliposomaldaunorubicininpediatricrelapsed/refractoryacutemyeloidleukemia:aphaseIBstudy.

Haematologica.2018;103:1484-92.

110.GargettT,AbbasMN,RolanP,PriceJD,GoslingKM,FerranteA,etal.PhaseItrialofLipovaxin-MM,anovel

dendriticcell-targetedliposomalvaccineformalignantmelanoma.Cancerimmunology,immunotherapy:CII.2018;

67:1461-72.

111.SchillerGJ,DamonLE,CoutreSE,HsuP,BhatG,DouerD.High-DoseVincristineSulfateLiposomeInjection,for

Advanced, Relapsed, or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in an

AdolescentandYoungAdultSubgroupofaPhase2ClinicalTrial.Journalofadolescentandyoungadultoncology.

2018;7:546-52.

112.Ohanian M, Tari Ashizawa A, Garcia-Manero G, Pemmaraju N, Kadia T, Jabbour E, et al. Liposomal Grb2

antisense oligodeoxynucleotide (BP1001) in patientswith refractory or relapsed haematologicalmalignancies: a

single-centre,open-label,dose-escalation,phase1/1btrial.TheLancetHaematology.2018;5:e136-e46.

113.EvansTRJ,DeanE,MolifeLR,LopezJ,RansonM,El-KhoulyF,etal.Phase1dose-findingandpharmacokinetic

studyoferibulin-liposomalformulationinpatientswithsolidtumours.Britishjournalofcancer.2019;120:379-86.

114.Mukai H, Kogawa T, Matsubara N, Naito Y, Sasaki M, Hosono A. A first-in-human Phase 1 study of

epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors.

InvestNewDrugs.2017;35:307-14.

115.LeeSW,KimYM,ChoCH,KimYT,KimSM,HurSY,etal.AnOpen-Label,Randomized,Parallel,PhaseIITrialto

Evaluate the Efficacy and Safety of a Cremophor-Free Polymeric Micelle Formulation of Paclitaxel as First-Line

TreatmentforOvarianCancer:AKoreanGynecologicOncologyGroupStudy(KGOG-3021).CancerResTreat.2018;

50:195-203.

116.FujiwaraY,MukaiH,SaekiT,RoJ,LinYC,NagaiSE,etal.Amulti-national, randomised,open-label,parallel,

phaseIIInon-inferioritystudycomparingNK105andpaclitaxelinmetastaticorrecurrentbreastcancerpatients.Br

JCancer.2019;120:475-80.